Project Summary/Abstract Substance use disorders represent a tremendous problem as nearly 27 million people in the United States struggle with these afflictions. Although some treatments are available, there is a substantial need to develop new therapies that address the underlying neurobiology of addiction. Most of the existing treatments have relied heavily upon the understanding of excitatory neurotransmitters, such as dopamine, serotonin, epinephrine, and norepinephrine; however, the potential of capitalizing on the central nervous system's inhibitory neurotransmitters is widely untapped. Modulation of the gamma-aminobutyric acid type-B (GABA-B) receptors represents an exciting, new intervention in the development of therapeutics for substance use disorders. This recent advance has been enabled through key distribution sites of the GABA-B receptors, along with the fact that GABA is the major inhibitory neurotransmitter in the central nervous system. Currently, only one FDA-approved pharmaceutical, baclofen, activates the GABA-B receptor, selectively; however, this drug does not accumulate in the brain which severely limits its potential in substance use disorders. We have recently discovered a new class of molecules that activates the GABA-B receptor but does not resemble the structure of GABA. This point is critically important as all of the other known agents, including baclofen, are structurally analogous to GABA; therefore, these compounds provide an excellent foundation to expand substantially the mechanisms for activating the GABA-B receptors. Furthermore, these findings are essential, because the GABA-B receptors are now known to modulate three different types of individual effectors. A provocative new area of pharmacological research is the development of biased agonists that distinguish across such effector pathways. Moreover, the discovery of biased agonists for each of three effectors of the GABA-B receptors would be powerful tools to down-regulate the other excitatory neurotransmitters. In this project, we aim to develop biased agonists as new chemical probes that exploit the central nervous system's inherent processes for inhibition through the GABA-B receptors. These agents would be powerful chemical tools to expand the understanding of neurobiology of substance abuse and may contribute to identifying novel treatment strategies for patients afflicted with these disorders. This proposal supports the AREA program goals by providing an opportunity for students at the University of Mississippi to learn modern technique in chemical synthesis and answer fundamental questions about the neurobiology of drug addiction.